Novel Potent Autophagy Inhibitors for Melanoma

针对黑色素瘤的新型有效自噬抑制剂

基本信息

批准号：
8920402
负责人：
JEFFREY D WINKLER
金额：
$ 45.63万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-16 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8920402
关键词：
Aminoquinolines Animal Model Antineoplastic Agents Apoptosis Autophagocytosis BRAF gene Binding Cancer Patient Cell Cycle Cell Cycle Arrest Cell Death Cells Chemicals Chloroquine Clinical Trials Development Distal Drug Combinations Drug Targeting Generations Genetic Genotype Goals Heme Hydroxychloroquine Immunotherapy In Vitro Instruction Investigation Knowledge Lead Libraries Lysosomes Malignant Neoplasms Mammalian Cell Measures Melanoma Cell Metabolic Mitochondria Modeling Molecular Target Neoplasm Metastasis Outcome Patient Selection Patients Pennsylvania Pharmaceutical Preparations Phase I Clinical Trials Play Process Proteins Proteomics Radiation therapy Role STAT3 gene Signal Transduction Small Interfering RNA Solubility Stress Structure System Testing Therapeutic Transgenic Mice Uncertainty University Hospitals Work Xenograft procedure analog aurora kinase base cancer cell cancer therapy chemotherapeutic agent chemotherapy cytotoxicity design drug candidate drug development in vivo indexing inhibition of autophagy inhibitor/antagonist kinase inhibitor lysosomal proteins mTOR inhibition melanoma novel novel therapeutics overexpression resistance mechanism response scaffold senescence targeted cancer therapy targeted treatment tumor tumor microenvironment

项目摘要

This project is directed toward the development of new chemotherapeutic agents for the treatment of melanoma based on the strategy of autophagy inhibition. Autophagy is an intracellular lysosome-dependent degradative process that protects cancer cells from metabolic and therapeutic stress within the tumor microenvironment. Autophagy inhibition with chloroqulne (CQ) derivatives augments the efficacy of many anticancer therapies, but has limited activity as a single agent therapy despite high levels of autophagy found in most tumors. Numerous clinical trials are testing the combination of variety of anticancer agents witJi hydroxychloroquine (HCQ), an analog of chloroqulne, but concerns have been raised about the potency of HCQ, and its pooriy understood mechanism of action. We have prepared dimeric bisaminoquinoline autophagy inhibitors that are ca. 10x more potent in vitro and in vivo than CQ or HCQ. Our hypothesis is that the new inhibitor LysOS is a more effective inhibitor of a specific unidentified target within the lysosome than standard monovalent CQ derivatives. Our specific aims are: 1) to identify the chemical determinants that characterize the most potent bisaminoquinoline autophagy inhibitors for melanoma cells; 2) to identify the molecular target of LysOS and second-generation bisaminoquinoline autophagy inhibitors in melanoma cells; and 3) to characterize the fates of melanoma cells treated with BAIs, alone and in combination with existing and novel targeted therapies for melanoma. The result of these studies will be the development of potent autophagy inhibitors with known molecular targets and mechanisms of action that will be promising drug development candidates for the treatment of melanoma.

该项目旨在开发新的化疗药物来治疗基于自噬抑制策略的黑色素瘤。自噬是细胞内溶酶体依赖性的保护癌细胞免受肿瘤内代谢和治疗应激的降解过程微环境。使用氯喹 (CQ) 衍生物抑制自噬可增强许多药物的功效抗癌疗法，但尽管发现了高水平的自噬，但作为单一药物疗法的活性有限在大多数肿瘤中。大量临床试验正在测试多种抗癌药物的组合羟氯喹（HCQ）是氯喹的类似物，但人们对其效力提出了担忧 HCQ 及其作用机制知之甚少。我们已经制备了二聚双氨基喹啉自噬抑制剂，其含量约为。体外效力增强 10 倍体内效果优于 CQ 或 HCQ。我们的假设是，新的抑制剂 LysOS 是一种更有效的抑制剂与标准单价 CQ 衍生物相比，溶酶体中特定的未识别靶标。我们的具体目标是：1）确定表征最有效的双氨基喹啉自噬的化学决定因素黑色素瘤细胞抑制剂； 2）确定LysOS和二代的分子靶点黑色素瘤细胞中的双氨基喹啉自噬抑制剂； 3) 描述黑色素瘤的命运单独使用 BAI 或与现有的和新型的黑色素瘤靶向疗法联合治疗的细胞。这些研究的结果将是开发具有已知分子的有效自噬抑制剂目标和作用机制将成为治疗该病的有希望的药物开发候选者黑色素瘤。